Atypical Response Properties of the Auditory Cortex of Awake MECP2-Overexpressing Mice

Abstract

Methyl-CpG binding protein 2 (MECP2) is a gene associated with DNA methylation and has been found to be important for maintaining brain function. In humans, overexpression of MECP2 can cause a severe developmental disorder known as MECP2 duplication syndrome. However, it is still unclear whether MECP2 overexpression also causes auditory abnormalities, which are common in people with autism. MECP2-TG is a mouse model of MECP2 duplication syndrome and has been widely used for research on social difficulty and other autism-like disorders. In this study, we used a combination of multiple electrophysiological techniques to document the response properties of the auditory cortex of awake MECP2-TG mice. Our results showed that while the auditory brainstem responses are similar, cortical activity patterns including local field potentials (LFPs), multiunit activity (MUA), and single-neuron responses differ between MECP2-TG and wild-type (WT) mice. At the single-neuron level, the spike waveform of fast-spiking (FS) neurons from MECP2-TG mice is different from that of WT mice, as reflected by reduced peak/trough ratios in the transgenic mice. Both regular-spiking (RS) and FS neurons exhibited atypical response properties in MECP2-TG mice compared with WT mice, such as prolonged latency and an elevated intensity threshold; furthermore, regarding the response strength to different stimuli, MECP2-TG mice exhibited stronger responses to noise than to pure tone, while this pattern was not observed in WT mice. Our findings suggest that MECP2 overexpression can cause the auditory cortex to have atypical response properties, an implication that could be helpful for further understanding the nature of auditory deficits in autism.

Excessive Formation and Stabilization of Dendritic Spine Clusters in the MECP2-Duplication Syndrome Mouse Model of Autism

“…Changes in input clustering could also contribute to changes in neuronal network correlation structure, excitability, and sensory processing (Lu et al, 2016;Nageshappa et al, 2016;Zhang et al, 2017;Zhou et al, 2019;Sun et al, 2020). We note that the above discussion depends on functional as well as cytological clustering of synaptic inputs, while at this point we only show differences in cytological clustering of newly formed spines in MECP2-dupication mice.…”

Auditory Dysfunction in Animal Models of Autism Spectrum Disorder

“…In contrast, cortical responses to noise are stronger, but delayed. Such abnormalities indicate a noise sensitivity phenotype associated to fast-spiking neurons that might be due to lack of cortical inhibition ( Zhou C. et al, 2019 ). Unlike many other ASD models, ABR is normal in Mecp2 overexpressing mice and cortical tonotopy does not seem to be affected ( Zhou C. et al, 2019 ).…”

Reciprocal control of translation and transcription in autism spectrum disorder

“…It has been suggested that MeCP2 acts in cortical PV interneurons to coordinate stimulus-specific, experiencedependent cortical plasticity, thereby reshaping the output of deep layer pyramidal neurons and that mutations in MECP2 disrupt cortical activity by arresting modulation of cortical PV networks (Lau et al, 2020). Consistent with these findings, MeCP2 overexpression results in atypical response properties of the auditory cortex in mice (Zhou et al, 2019a).…”